Project Summary Nerve injury can occur due to trauma, chronic compression or disease processes such as diabetes or tumors and have a tremendous socioeconomic impact from loss of work and healthcare costs. There is still a clinical need to improve recovery from nerve injuries, and a new nerve conduit drug delivery device that addresses this clinical need is the focus of the present proposal. Our group has developed a patented drug-delivering conduit for use in peripheral nerve surgery that can release growth factors and/or small molecules in a controlled manner to the regenerating nerve and can be used in a variety of peripheral nerve injury or repair applications. By taking advantage of the simple physical process of diffusion we have designed a hole-based drug delivery system that demonstrates controlled release. In this proposal we plan to use our unique nerve conduit device to locally deliver a neurotrophic small molecule, FK506. The overall objective is to demonstrate that our patented nerve conduit, that locally releases FK506, can enhance functional recovery when used i) to bridge a nerve gap and ii) in conjunction with autologous nerve graft repair of a peripheral nerve injury in a rat sciatic nerve model. In Aim 1a we will utilize rapid prototyping to manufacture a device that can release FK506 for 60 days at a concentration (0.1-10ng/mL) that has been shown to be neurotrophic. We will evaluate the FK506 release kinetics over the release period using a commercially available ELISA. We will then evaluate (Aim 1b) the efficacy of our nerve guide drug delivery device to improve functional outcomes, as measured by sciatic functional index and muscle atrophy, in two different rat sciatic nerve surgical repair strategies: 1) to bridge a nerve gap and 2) in conjunction with autologous nerve graft repair. We will evaluate the primary outcome variables (sciatic functional index and muscle atrophy) and secondary measures including nerve histomorphometry, neuromuscular junction connectivity, and electrophysiology at 100 days post-surgery. We expect to see greater improvements in functional recovery when the sciatic nerve injury is repaired with the combination of standard surgical repair AND local FK506 delivery compared to standard repair alone. We have set to two primary ?go, no go? milestones to provide sufficient evidence for continuation of the commercialization plan and warrant Phase II funding: 1) Our FK506 releasing device will result in statistically greater improvements in functional recovery (gait and muscle mass) than an FDA approved device and equivalent to an autograft in bridging a 2cm nerve gap and 2) Our FK506 device combined with an autograft will have statistically better functional outcomes than treatment of a 2cm gap injury with autograft alone. This approach of locally releasing FK506 from our novel drug-delivering conduit could potentially transform current nerve repair strategies and dramatically improve the functional outcomes following peripheral nerve repair.